Abstract: Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and β-MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling.
Keywords: cardiac hypertrophy; AKIP1; Akt; kinase; remodeling
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Yu, H.; Tigchelaar, W.; Lu, B.; van Gilst, W.H.; de Boer, R.A.; Westenbrink, B.D.; Silljé, H.H.W. AKIP1, a Cardiac Hypertrophy Induced Protein that Stimulates Cardiomyocyte Growth via the Akt Pathway. Int. J. Mol. Sci. 2013, 14, 21378-21393.
Yu H, Tigchelaar W, Lu B, van Gilst WH, de Boer RA, Westenbrink BD, Silljé HHW. AKIP1, a Cardiac Hypertrophy Induced Protein that Stimulates Cardiomyocyte Growth via the Akt Pathway. International Journal of Molecular Sciences. 2013; 14(11):21378-21393.
Yu, Hongjuan; Tigchelaar, Wardit; Lu, Bo; van Gilst, Wiek H.; de Boer, Rudolf A.; Westenbrink, B. D.; Silljé, Herman H.W. 2013. "AKIP1, a Cardiac Hypertrophy Induced Protein that Stimulates Cardiomyocyte Growth via the Akt Pathway." Int. J. Mol. Sci. 14, no. 11: 21378-21393.